β-Amyloid Is Transmitted via Neuronal Connections along Axonal Membranes

Objective: beta-amyloid plaque is a critical pathological feature of Alzheimer disease. Pathologic studies suggest that neurodegeneration may occur in a retrograde fashion from axon terminals near beta-amyloid plaques, and that plaque may spread through brain regions. However, there is no direct experimental evidence to show transmission of beta-amyloid. Methods: Microscopic imaging data of beta-amyloid transmission was acquired in cortical neuron cultures from Sprague-Dawley rat embryos using polydimethylsiloxane (PDMS) microfluidic culture chambers and in brain sections from in vivo beta-amyloid injection. Results: We present direct imaging evidence in cultured cortical neurons, using PDMS microfluidic culture chambers, that beta-amyloid is readily absorbed by axonal processes and retrogradely transported to neuronal cell bodies. Transmission of beta-amyloid via neuronal connections was also confirmed in mouse brain. beta-Amyloid absorbed by distal axons accumulates in axonal swellings, mitochondria, and lysosomes of the cell bodies. Interestingly, dynasore, an inhibitor of dynamin, which is a protein indispensable for endocytosis, did not prevent retrograde transport of beta-amyloid, indicating that beta-amyloid is absorbed onto axonal membranes and transmitted via them to the cell body. Dynasore did decrease the transneuronal transmission of beta-amyloid, suggesting that this requires the internalization and secretion of beta-amyloid. Interpretation: Our findings provide direct in vitro and in vivo evidence for spreading of beta-amyloid through neuronal connections, and suggest possible therapeutic approaches to blocking this spread.